ABSTRACT
The trefoil factor family (TFF) comprises a group of small peptides which are highly expressed in tissues containing mucus-producing cells - especially in the mucosa lining the gastrointestinal tract. The peptides seem crucial for epithelial restitution and may work via other pathways than the conventional factors involved in restitution. In vitro studies have shown that the TFFs promote restitution using multiple mechanisms. The peptides also have other functionalities including interactions with the immune system. Moreover, therapeutic effects of the TFFs have been shown in several animal models of gastrointestinal damage. Still it is not clear which of their in vitro properties are involved in the in vivo mode of action. This review describes the TFF family with emphasis on their biological properties and involvement in mucosal protection and repair.
Subject(s)
Mucous Membrane , Peptides/physiology , Regeneration , Animals , Epithelium/pathology , Humans , Inflammation/pathology , Mucous Membrane/pathology , Peptides/genetics , Tissue Distribution , Trefoil Factor-2ABSTRACT
BACKGROUND: Activation of platelets with a combination of collagen and thrombin generates a subpopulation of highly procoagulant 'coated' platelets characterized by high surface expression of fibrinogen and other procoagulant proteins. OBJECTIVES: To analyze the interaction of recombinant factor VIIa (rFVIIa) with coated platelets. METHODS AND RESULTS: rFVIIa localized to the coated platelets in flow cytometry experiments, while minimal rFVIIa was found on platelets activated with adenosine diphosphate, thrombin or via glycoprotein VI individually, and essentially no rFVIIa was found on non-stimulated platelets. Removal of the gamma-carboxyglutamic acid (Gla) domain of rFVIIa, and addition of EDTA, annexin V or excess prothrombin inhibited rFVIIa localization to the coated platelets, indicating that the interaction was mediated by the calcium-dependent conformation of the Gla domain and platelet exposure of negatively charged phospholipids. A reduced level of platelet fibrinogen exposure was observed at hemophilia A-like conditions in a model system of cell-based coagulation, indicating that coated platelet formation in hemophilia may be diminished. Addition of rFVIIa dose-dependently enhanced thrombin generation and partly restored platelet fibrinogen exposure. CONCLUSIONS: The data suggest that rFVIIa localized preferentially on platelets activated with dual agonists, thereby ensuring enhanced thrombin generation localized at the site of injury where both collagen and tissue factor are exposed, the latter ensuring the formation of thrombin necessary for coated platelet formation.
Subject(s)
Blood Platelets/metabolism , Coagulants/chemistry , Factor VIIa/biosynthesis , Platelet Membrane Glycoproteins/metabolism , Thrombin/physiology , 1-Carboxyglutamic Acid/chemistry , Binding Sites , Blood Coagulation , Collagen/metabolism , Flow Cytometry , Hemophilia A/pathology , Humans , Phospholipids/chemistry , Protein Structure, Tertiary , Thrombin/metabolism , Thromboplastin/metabolismABSTRACT
BACKGROUND AND PURPOSE: Trefoil factors (TFFs) secreted by mucus-producing cells are essential for the defence of the gastrointestinal mucosa. TFFs probably influence the viscoelastic properties of mucus, but this has not been demonstrated in vivo. We therefore studied the gastric secretion of systemically administered TFF2 and TFF3, and their influence on the viscosity of the secretions. EXPERIMENTAL APPROACH: Mice and rats under general anaesthesia were injected intravenously with human (h) TFF2, hTFF3 (5 mg kg(-1) to mice and 25 mg kg(-1) to rats), murine (m) (125)I-TFF3, or (125)I-hTFF3 (300,000 cpm, mice only). The appearance of TFFs in the gastric mucosa and luminal secretions was analysed by autoradiography, gamma-counting, and ELISA, and the viscosity by rheometry. KEY RESULTS: (125)I-mTFF3 and (125)I-hTFF3 were taken up by secretory cells of the gastrointestinal tract and detected at the gastric mucosal surface 15 min after injection. Stressing the stomach by carbachol (3.5 microg kg(-1)) and pyloric ligation significantly increased the uptake. Injected hTFF2, hTFF3, and mTFF3 were retrieved from the gastric contents after 4 h. In rats, an approximately seven-fold increase in the viscosity was detected after injection of TFF2 compared to the controls, whereas TFF3 did not increase the viscosity. In mice, TFF2 increased the viscosity approximately 4-fold. CONCLUSIONS: These data indicate that systemically administered TFFs are transferred to the gastric lumen in a biologically active form.
